Vitamin D compounds are known to show a wide variety of physiological activities such as calcium metabolism regulation, growth inhibition or differentiation induction of tumor cells or the like, immunoregulation, etc.
Vitamin D compounds and their intermediates are commonly synthesized by using methods based on the Wittig-Horner reaction.
The Wittig-Horner reaction generally refers to a series of reactions where a Wittig reagent obtained from an alkyl halide and a triphenyl phosphate ester is reacted with a strong base to form a phosphonium ylide, the ylide adds to an aldehyde or ketone to form an adduct and, then, a phosphine oxide is removed from the adduct (oxaphosphetane) to give an olefin.
The Wittig-Horner reaction is performed by adding a base dropwise to a Wittig reagent to produce a ylide and then adding a ketone or aldehyde to the ylide, or by mixing a Wittig reagent and a ketone or aldehyde and then adding a base dropwise to the resulting mixture (Blahr L. et al., Steroides, 66, 2001, 539) or other methods, among which only the first method is used for the synthesis of vitamin D compounds. This is because the second method or other methods cannot be expected to provide a sufficient yield due to the epimerization of a ketone used as a starting material or the nucleophilic reaction of the anion of a base added (e.g., n-butyl anion is formed when n-butyl lithium is added as a base) to the carbonyl group on the ketone or aldehyde, whereby the ketone or aldehyde is consumed.
Specifically, the synthesis of a vitamin D compound begins by adding a strong base such as n-butyl lithium, phenyl lithium, methyl lithium or lithium diisopropylamide dropwise to a Wittig reagent which is an A-ring intermediate of the vitamin D in tetrahydrofuran at an extremely low temperature, normally −78° C., to produce a ylide. Then, a solution of a ketone which is a CD-ring intermediate of the vitamin D in tetrahydrofuran is added to the ylide at an extremely low temperature, normally −78° C. Then, the mixed solution is stirred between −78° C. and room temperature to form a trans-diene structure characteristic of vitamin D. This method is widely used for synthesizing various vitamin D compounds and their intermediates because a relatively good yield and high stereoselectivity can be obtained (Baggiolini E. et al., J. Am. Chem. Soc., 104,1982, 2945, Baggiolini E. et al., J. Org. Chem., 51, 1986, 3098, Zhu G. et al., Chem. Rev., 95, 1995, 1877, Norman A. et al., J. Med. Chem., 43, 14, 2000, 2719, Shiuey S. et al., J. Org. Chem., 55, 1990, 243, Sicinski, R. et al., J. Med. Chem., 41, 23, 1998, 4662, Wu Y. et al., Bioorg. Med. Chem. Lett., 12, 12, 2002, 1633, Kutner A. et al., Bioorg. Chem., 23, 1, 1995, 22). This method is also used for synthesizing vitamin D compounds and their intermediates using an aldehyde instead of a ketone as a CD-ring intermediate (Wu Y. et al., Bioorg. Med. Chem. Lett., 12, 12, 2002, 1633).
A typical example of a synthetic scheme of vitamin D compounds via the Wittig-Horner reaction is shown below.

It is known that several side reactions occur during the Wittig-Horner reaction. One of them is induced by moisture inclusion so that the ylide is lost. Another side reaction is epimerization of the ketone which is caused by rise of the reaction temperature (Baggiolini E. et al., J. Am. Chem. Soc., 104, 1982, 2945, Baggiolini E. et al., J. Org. Chem., 51, 1986, 3098, Peterson P. et al., J. Org. Chem., 51, 1986, 1948). Still another side reaction is nucleophilic addition to the carbonyl group on the ketone or aldehyde. If these side reactions occur, the yield of vitamin D compounds decreases.
Two side reactions accompanying the Wittig-Horner reaction are shown below.

In order to avoid these side reactions to afford intended vitamin D compounds with high yield, in conventional methods for vitamin D synthesis, it was necessary to prevent moisture inclusion into the reaction system and to perform mixing procedures under low temperature conditions. In addition to the step of adding a solution of a ketone in tetrahydrofuran to the produced ylide, which must be performed at low temperature, normally −78° C., to prevent epimerization, the preceding step of adding a base such as n-butyl lithium dropwise to a Wittig reagent has also been conventionally performed at a low temperature, normally −78° C. Under such low temperature conditions, moisture inclusion due to condensation or the like and temperature rise which may induce side reactions would be more likely to occur. Hence, very complex mixing procedures have been required to prevent the side reactions.
In an industrial large-scale synthesis of vitamin D compounds, tremendous amounts of cost for facility, labor, energy or the like and time have been required to prevent moisture inclusion and to maintain an extremely low temperature environment. On the other hand, in a so-called laboratory scale synthesis of vitamin D compounds where a small amount of compound on the order of 10 to 20 mg is synthesized, the yield was very low or no intended product could be obtained (Posner G. et al., J. Med. Chem., 35, 1992, 3280). This is because it is difficult to prevent moisture inclusion and maintain an extremely low temperature environment even by using a syringe or cannula or the like and the above side reactions are more likely to occur especially due to complex mixing procedures during the small-scale synthesis on the order of 10 to 20 mg.
It is believed that intended vitamin D compounds could be theoretically obtained in good yield by using equivalent amounts of a Wittig reagent and a ketone or aldehyde. However, conventional methods have failed to sufficiently prevent side reactions and have required much cost and time to sufficiently prevent them as described above, and therefore, an excess of about 0.5 equivalents to 1 equivalent of either a Wittig reagent or a ketone or aldehyde has been typically used to prevent the yield loss resulting from side reactions, which has further added production costs.
Unreacted Wittig reagent and ketone or aldehyde can be recovered by a silica gel column or the like to avoid the waste of starting materials (Baggiolini E. et al., J. Org. Chem., 51, 1986, 3098, Hatakeyama S. et al., Bioorg. Med. Chem. 9, 2001, 403), but recovery procedures require cost and time and epimerized ketones are often unrecoverable.